Noriko Hotta

Distinct Impact of Imatinib on Growth at Prepubertal and Pubertal Ages of Children with Chronic Myeloid Leukemia

OBJECTIVE To determine the extent of growth impairment resulting from imatinib treatment in children with chronic myeloid leukemia (CML). STUDY DESIGN Clinical records of 48 chronic-phase CML children administered imatinib as the first-line therapy between 2001 and 2006 were analyzed retrospectively. Cumulative change in height was assessed using the height height-SDS and converted height data from age- and sex-adjusted Japanese norms. RESULTS A decrease in height-SDS was observed in 72.9% of children, with a median maximum reduction in height-SDS of 0.61 during imatinib treatment. Median follow-up time was 34 months (range, 10-88 months). Growth impairment was seen predominantly in children who started imatinib at a prepubertal age compared with those who started at pubertal age. Growth velocity tended to recuperate in prepubertal children with growth impairment, as they reached pubertal age, suggesting that imatinib had little impact on growth during puberty. CONCLUSIONS Growth impairment was a major adverse effect of long-term imatinib treatment in children with CML. We report the distinct inhibitory effect of imatinib on growth in prepubertal and pubertal children with CML. We should be aware of growth deceleration in children, especially in young children given imatinib before puberty and subjected to prolonged exposure.

Clinical impact of HLA-DR15, a minor population of paroxysmal nocturnal haemoglobinuria-type cells, and an aplastic anaemia-associated autoantibody in children with acquired aplastic anaemia

Aplastic anaemia (AA) is defined as a pancytopenia caused by bone marrow failure, and its pathogenesis is thought to involve autoimmune processes. Several predictive markers of the response to immunosuppressive therapy (IST) have been proposed, which appear to reflect the immune pathophysiology. We prospectively investigated the presence of human leucocyte antigen (HLA)‐DR15, a minor population of paroxysmal nocturnal haemoglobinuria (PNH)‐type cells, and antibodies to the recently identified autoantigen postmeiotic segregation increased 1 (PMS1) in 103 children with AA enrolled in a multicentre study. In contrast to adults, children with AA did not show an increased frequency of HLA‐DR15. In addition, a sensitive flow cytometric assay revealed that children with AA have a much lower prevalence of PNH‐type cells (21·4%) than reported for adults with this disease. An immunoblotting assay detected anti‐PMS1 antibody in 15 of 103 (14·6%) of the children. Finally, the response rate to IST was not significantly different between patients with and without DR15 (45·5% vs. 54·0%), PNH‐type cells (68·2% vs. 53·1%) or anti‐PMS1 antibody (40·0% vs. 59·1%). The current study did not confirm a correlation between these markers and the response to IST, suggesting that there is a difference in the pathophysiologies of adult and paediatric AA.

Outcome of 125 Children with Chronic Myelogenous Leukemia Who Received Transplants from Unrelated Donors: The Japan Marrow Donor Program

Because of a small number of patients, only a few studies have addressed the outcome of bone marrow transplantation (BMT) in children with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML), who receive graft from a volunteer-unrelated donor (VUD), especially after practical application of imatinib mesylate. The outcomes of BMT from a VUD in 125 children with Ph+ CML were retrospectively reviewed. Patients were identified through the Japan Marrow Donor Program as having undergone BMT between 1993 and 2005 and were aged 1-19 years at the time of transplant (median age, 14 years). The probabilities of 5-year overall survival (OS) and leukemia-free survival (LFS) were 59.3% and 55.5%, respectively. Multivariate analysis identified the following unfavorable survival factors: infused total nucleated cell dose<314 x 10(6) /kg (relative risk [RR]=2.43; 95% confidence interval [CI]=1.33-4.44; P=.004), advanced phase (RR=2.43; 95% CI=1.37-4.31; P=.004), and no major cytogenetic response (MCyR) at the time of BMT (RR=6.55; 95% CI=1.98-21.6; P=.002). Of the 17 patients treated with imatinib, 15 (88%) achieved MCyR at the time of BMT, and this group had an excellent 5-year OS of 81.9%. Disease phase, infused total nucleated cell dose, and cytogenetic response were independent risk factors for survival of unrelated BMT. These findings provide important information for assessing the indications for and improving outcome in unrelated BMT for the treatment of pediatric CML.

Clinical and genetic analyses of presumed shwachman-diamond syndrome in Japan

Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, and skeletal abnormalities. SBDS was identified as a causative gene for SDS in 2003, and genetic analyses of SDS have been performed.We performed genetic analysis of 13 Japanese patients with presumed SDS and found that 10 of them had SBDS mutations. Most patients had recurrent mutations (181-184TA→CT and 258+2T→C); however, 2 patients had unique mutations (259-1G→A and 428C→G). Although genetic analysis is useful for definitive diagnosis and for genetic counseling of SDS patients and families, SDS appears to be a genetically heterogeneous disorder. In addition, presumed SDS patients without SBDS mutations may be included in other disorders.

Randomized trial to compare LSA2L2-type maintenance therapy to daily 6-mercaptopurine and weekly methotrexate with vincristine and dexamethasone pulse for children with acute lymphoblastic leukemia.

A total of 201 pediatric cases of acute lymphoblastic leukemia were treated with the ALL‐96 protocol by the Kyushu‐Yamaguchi Childrens Cancer Study Group.

Leukostasis in Children and Adolescents with Chronic Myeloid Leukemia: Japanese Pediatric Leukemia/Lymphoma Study Group

The details of leukostasis in children and adolescents with chronic myeloid leukemia (CML) are unknown. This study determined the characteristics of leukostasis in children and adolescents with CML.

Sequential use of second-generation tyrosine kinase inhibitors following imatinib therapy in pediatric chronic myeloid leukemia: A report from the Japanese Pediatric Leukemia/Lymphoma Study Group

The details of the sequential use of imatinib for first‐line treatment followed by second‐generation tyrosine kinase inhibitors (2G‐TKIs) for pediatric chronic myeloid leukemia (CML) are still unknown. This study analyzed clinical responses and adverse effects of the use of 2G‐TKIs following imatinib in pediatric chronic phase (CP)‐CML.

Flow cytometric analysis as an additional predictive tool of treatment response in children with chronic-phase chronic myeloid leukemia treated with imatinib

Bone marrow samples of newly diagnosed children with chronic‐phase chronic myeloid leukemia (CML) were obtained at diagnosis and after imatinib initiation and stained with anti‐human CD34, CD38, CD123, CD45RA, cMpl, and lineage antibodies. Flow cytometric analysis revealed that granulocyte macrophage progenitor predominance in CML progenitors at diagnosis and elevated cMpl expression in bone marrow progenitors at 3 months may predict poor outcome in children with chronic‐phase CML treated with imatinib. We recommend flow cytometric analysis of bone marrow in the early phase of treatment, as it is a convenient tool that may predict treatment response and guide CML management.